Is MCM3 p.Pro718Ser (c.2152C>T) pathogenic?

MCM3 p.Pro718Ser (c.2152C>T) is classified Uncertain significance in MCM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: likely benign (0.2135); Very rare (popmax 0.00407%, nfe).

How common is MCM3 p.Pro718Ser (c.2152C>T) in the general population?

MCM3 p.Pro718Ser (c.2152C>T) is very rare (popmax 0.00407%, nfe) (gnomAD).

What do computational predictors say about MCM3 p.Pro718Ser (c.2152C>T)?

AlphaMissense predicts likely benign (score 0.2135) — an in-silico prediction, not a clinical call.

MCM3 p.Pro718Ser

c.2152C>T · VCV3871266

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2135 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00407%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2135	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -5.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 7,853 bp · p 0.13 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00407% European (non-Finnish) · 48/1,179,834 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00297% 48/1,613,782 alleles · very rare exomes 45/1,461,622 · genomes 3/152,160 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MCM3
Protein: p.Pro718Ser
Coding: c.2152C>T
MANE Select: NM_002388
Type: single nucleotide variant
Location: chr6:52266617 (GRCh38)
Gene constraint: LOEUF 0.812 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.04 · 29 PDB
Residue 718: the 'disordered' region

Full MCM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MCM3 p.Ala262Ser Uncertain significance ★ ⚠ same type
MCM3 p.Ala278Thr Uncertain significance ★ ⚠ same type
MCM3 p.Ala300Gly Uncertain significance ★ ⚠ same type
MCM3 p.Ala509Val Uncertain significance ★ ⚠ same type
MCM3 p.Ala528Gly Uncertain significance ★ ⚠ same type
MCM3 p.Ala608Thr Uncertain significance ★ ⚠ same type
MCM3 p.Arg114Trp Uncertain significance ★ ⚠ same type
MCM3 p.Arg138Cys Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mcm3-p-pro718ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown